The present invention is generally in the area of prevention of surgical adhesion.
Adhesions are a common complication of surgery. They may develop in a variety of areas in the body, and are characterized in that tissues which were separate before surgery become bonded together in the process of healing. The type and degree of damage caused by adhesions is variable, ranging from life-threatening, as in the intestines due to blockage, to extremely disabling, as in tendons or spinal cord, to chronic pain and infertility in the pelvic cavity, to being obstructive of further surgery in the pericardium. Postoperative formation of pelvic adhesions remains a serious problem in patients undergoing gynecological surgery and is a principal cause of infertility. In general, the most common causes of pelvic adhesions in women are prior surgery, endometriosis and pelvic inflammatory disease.
Injury to intact peritoneum as a result of surgical insult or infection begins a cascade of pathophysiological events. Within three hours of surgical insult or infection, there is damage to vasculature, resulting in increased vessel permeability, and an inflammatory response, resulting in further vascular damage due to ischemia and reperfusion injury. The exudate of serosanguionous fluid and fibrin matrix leads to further ischemia, resulting in persistence of fibrin matrix and collagenous adhesions, as well as fibrinolysis to yield fibrin split products, absorption of fibrin matrix, and normal repairs. This cascade includes the expected events associated with inflammation including both neutrophil and macrophage migration to the site of inflammation. Associated with this cell migration is a rapid respiratory burst leading to the generation of oxygen radicals at the site of inflammation. In the absence of sufficient free radical scavengers, high concentrations of oxygen radicals are capable of damaging the surrounding intact cells, including those responsible for vascular integrity. This increased permeability of blood vessels can lead to exudation of proteinaceous serosanguinous fluid which serves as a matrix for fibrinous adhesions. In addition, increased vascular permeability leads to local interruption of blood flow and eventual cell death in the vessels comprising the vascular supply. Reperfusion of tissues, following this ischemic event, leads to further generation of oxygen radicals and, ultimately, further exacerbates the degree of fibrinous adhesion formation.
Under normal circumstances, the fibrinolytic capacity of plasminogen activator activity (PAA) leads to the absorption of such fibrinous deposits and to conventional peritoneal healing. However, in the presence of severe tissue injury (e.g. following surgical trauma), a decrease in PAA leads to abnormally persistent fibrin deposits and, ultimately, mature collagenous adhesions. Meticulous dissection (i.e. adhesiolysis) continues to be the most widely accepted treatment for existing adhesions. A substantial fraction of surgery therefore requires follow-up surgery to repair the effects of the adhesions. This procedure is generally called xe2x80x9cadhesiolysisxe2x80x9d; in some organ systems, the procedure has specific names, such as xe2x80x9ctenolysisxe2x80x9d in the freeing of tendons.
The list of potential therapeutic modalities used in prevention of formation and reformation of adhesions is extensive and includes infusion of liquids into the pelvic cavity at the time of surgery, mechanical barriers between two opposing surfaces, and intravenously injected or topically applied pharmacologic agents (Tulandi, xe2x80x9cEffects of Ringer""s Lactate on Postsurgical Adhesion. In: Diamon, et al., eds, vol. 381, Progress in Clinical and Biological Research (NY, Wiley-Liss 1993) 59-63; Schwartz, et al., Sem. in Repro. Endocrin. 9:89-99 (1991); Pjilman, et al., Eur. J. Ost and Gyn. Repro. Biol. 53:155-163 (1994); and Monk, et al., Am. J. Obstet. Gynecol. 170:1396-1403 (1994). However, the incidence of symptomatic adhesion formation remains high, and the clinical need for adhesion prevention still exists.
Therapies of various sorts have been used to prevent the initial formation of adhesions (xe2x80x9cprimaryxe2x80x9d adhesions). These include lavage with water-soluble polymers and/or biologically active molecules (xe2x80x9cdrugsxe2x80x9d), which are usually not very effective. However, the use of superoxide dismutate (SOD) combined with catalase prevented or diminished endometriosis-induced adhesions in rabbits in a study by Poretz et al, (Int. J. Fertil. 36:39-42, 1991). Permanent mechanical barriers, such as Teflon(trademark) sheets, can be effective but are difficult to remove; and degradable barriers such as oxidized cellulose (InterCeed(trademark), Johnson and Johnson) and degradable polymeric gels (Sawhney et al, 1993; Hill-West et al 1994) can have significant utility in the prevention of primary adhesions. Tsimoyiannis et al (Acta Chir. Scand. 155: 171-174, 1989) reported reductions of about 50% in the incidence and 50-70% in the severity of ischemia-related induction of primary adhesions in rats, after administration of SOD, catalase, DMSO (dimethylsulfoxide) or allopurinol as an intravenous bolus before surgery.
It has been hypothesized that the commonality of these drugs is in their inhibition of the pathway leading to oxidative damage to tissue. SOD, catalase and DMSO each directly destroy active oxygen species, such as superoxide, peroxide, or hydroxyl radical; allopurinol is known to inhibit the enzyme xanthine oxidase, which produces hydrogen peroxide. These compounds which directly or indirectly inhibit the effect of active oxygen species on tissue are referred to herein as xe2x80x9cactive oxygen inhibitorsxe2x80x9d, or AOIs. Superoxide dismutase (SOD, dimer MW=31.5 kDa, tetramer=67 kDa) has been efficacious in the treatment of ischemic/reperfusion events in a wide variety of tissues including brain, kidney, and heart (Schneider, et al., Fr. Rad. Biol. and Med. 3:21-26 (1987); Zimmerman, et al., Am. J. Med. Sci. 307:284-292 (1994); Voogd, et al., Fr. Rad. Biol. and Med. 11:71-75 (1991); Fridovich, Arch. Bioch. and Biophys. 247:1-11 (1986); Kontos, et al. CNS Trauma 3:257-263 (1986)). There is also evidence that SOD can be effective in the prevention of pelvic adhesions (Tsimoyiannis, et al., Acta Chir. Scand. 155:171-174 (1989); Portz, et al., Int. J. Fert. 36:39-42 (1991); O""Leary, et al., Ann. Surg. June:693-698 (1987)). However, efficacy using SOD has been limited, due to its rapid elimination from the bloodstream (Petkau, et al., Res. Commun. Chem. Pathol. Pharmacol. 15:641-654 (1976); Odlund, et al., Pharmacol. Toxic 62:95-100 (1988)). Improved efficacy has resulted from strategies for increasing SOD content in the bloodstream including chemical modification to reduce the rate of elimination (Pyatak, eta l., Res. Comm. Chem. Path. Pharm. 29:113-127 (1980); Hill-West, et al. Obstet. Gynecol. 83:59-64 (1994)) and frequently repeated injections (O""Leary, et al., 1987).
Removal of adhesions once formed is substantially more difficult than prevention of adhesion formation. Unfortunately, formulations which effectively prevent primary adhesions (e.g., Hill-West et al, 1994) can be substantially less effective in preventing re-adhesion after adhesiolysis (xe2x80x9csecondaryxe2x80x9d adhesions). While the exact biological differences between primary and secondary adhesions are not known, it is possible that the formation of primary adhesions depends on the persistence of fibrin bridges between the disjoint parts, which are subsequently colonized by other cells and develop into permanent vascularized tissue. Anything disrupting formation or stabilization of the initial fibrin bridge would tend to prevent primary adhesion formation. Secondary ahesions, however, maybe the result of the normal healing process applied to injured pre-existing tissue, i.e. the lysed primary adhesion. The healing process, while not yet understood in detail, involves the mobilization of several cell types and the formation of new collagen, and typically has initial stages lasting for up to two weeks followed by several months of maturation to obtain full repair. Because of these differences, it is possible that treatments effective in primary adhesion prevention will require enhancement to prevent reformation of adhesions after adhesiolysis.
In summary, there have been no reports of compositions totally effective in eliminating adhesions, especially in patients in which the injury is repeated, as in the case of patients having had multiple surgeries.
It is therefore an object of the present invention to provide a method and compositions for preventing adhesions following surgery or infection.
SOD and other active oxygen inhibitors are directly applied in combination with a barrier material at local sites of tissue injury to prevent or decrease formation of adhesions and undesirable proliferation of cells. Preferred barrier materials are polymeric hydrogels providing controlled release of AOI which are directly applied to the afflicted tissue.
Examples demonstrate the effects of SOD on pelvic adhesions in the rat when administered by intraperitoneal (I.P.) bolus and by localized sustained release from a topically applied hydrogel system.